Chronic hepatitis B virus (HBV) infection affects over 400 million people worldwide and is associated with a 100- to 200-fold greater risk of developing hepatocellular carcinoma (HCC) (Melegari et al. (1998) J. Virol. 72(3):1737-1743; Beasley et al. (1981) Lancet 2:1129-1133). HBV, as well as other mammalian hepadnaviruses, contains a highly conserved open reading frame encoding the HBV x protein (HBx). HBx is required to establish a productive infection in the liver and is known to function as an activator of mitogenic pathways and as a transcriptional transactivator. The ability of HBx to alter signaling pathways involved in cellular growth and differentiation and apoptosis suggested a role for HBx in the development of HCC in the livers of persistently infected patients (Melegari et al. (1998) J. Virol. 72(3):1737-1743).
Hepatitis B X-interacting protein (HBXIP) was first identified as a cellular protein that interacts with HBx. Expression of HBXIP is observed in nearly all tissues, not just the liver (Melegari et al. (1998) J. Virol. 72(3):1737-1743). Elevated levels of HBXIP have been found in both cancerous and non-malignant liver tissue of humans with chronic HBV infection, relative to normal hepatic tissue. Little is known about the role of HBXIP; however, HBXIP has been shown to interact with survivin, an anti-apoptotic protein that is over-expressed in most types of human cancer (Marusawa et al. (2003) EMBO J. 22(11):2729-2740). Survivin normally plays an essential role in chromosome segregation and cytokinesis during cell division. When survivin is overexpressed, such as in tumors, it manifests an anti-apoptotic role. Marusawa et al. demonstrate that survivin forms a complex with HBXIP and that these complexes inhibit apoptosis by binding to pro-caspase 9, which prevents its recruitment to Apaf1, thus halting the apoptotic pathway. Neither survivin nor HBXIP alone were capable of preventing apoptosis, suggesting that HBXIP functions as a survivin co-factor. This study suggests that HBx regulates apoptotic pathways during viral infection via HBXIP and survivin and points to HBXIP as an important factor in the development of HCC and other types of cancer.
U.S. pre-grant publication 2004-0138119 discusses inhibiting interaction of survivin and HBXIP to modulate apoptosis. Disclosed methods of inhibiting interaction include survivin- or HBXIP-specific antibodies, molecular decoys, specific inhibitors, antisense and siRNAs.
Little is known about the cellular functions of HBXIP and how it contributes to the development of HCC and other types of cancer. However, HBXIP appears to influence apoptotic pathways, making it an excellent target for anti-cancer therapeutics. Thus, there remains a significant need for specific inhibitors of HBXIP.